Kim C-D, Cho Y-J, Park S-H, Ha S-W, Lee E-G, Kim Y-J, Kwon T-H, Kim I-S, Kim Y L
Kyungpook National University School of Medicine, Department of Internal Mediicne, Daegu, Republic of Korea.
Transplant Proc. 2006 Jun;38(5):1314-9. doi: 10.1016/j.transproceed.2006.02.070.
Transforming growth factor (TGF)-beta is involved in the pathogenesis of chronic cyclosporine nephrotoxicity (CyAN). Since the expression of TGF-beta induced gene h3 (betaig-h3) is up-regulated by TGF-beta, we evaluated the potential role of betaig-h3 as a sensitive urinary marker to monitor the progression/regression of chronic CyAN. Urinary betaig-h3 levels were determined using an enzyme-linked immunosorbent assay in nine patients with chronic CyAN and 13 patients with stable graft function. We scored the extent of tubulointerstitial fibrosis (TIF) and using immunoperoxidase labeling, determined betaig-h3 expression in renal tissues of patients with chronic CyAN. Urinary betaig-h3 excretion was higher in chronic CyAN compared to control subjects (173.4+/-26.0 vs 62.6+/-5.0 ng/mg creatinine, P<.01). In chronic CyAN, the degree of TIF correlated with increased urinary betaig-h3 levels (r=.785, P<.05). In kidneys with chronic CyAN, betaig-h3 labeling was more prominent at the basement membranes (BM) of the tubules where inflammatory cells had infiltrated the surrounding interstitium. Moreover, the BM of the atrophied tubules and their surrounding interstitium were strongly labeled. Urinary betaig-h3 levels decreased from 173.4+/-26.0 to 64.9+/-14.4 ng/mg creatinine at 1 month after discontinuation of CyA or reduction in CyA dosage (P<.01) despite unchanged serum creatinine levels. Urinary betaig-h3 levels increased in patients with chronic CyAN and decreased after discontinuation or reduction of CyA dosage. Our results suggested that urinary betaig-h3 levels could be used as a sensitive urinary marker to monitor the progression or regression of chronic CyAN.
转化生长因子（TGF）-β参与慢性环孢素肾毒性（CyAN）的发病机制。由于TGF-β诱导基因h3（βig-h3）的表达受TGF-β上调，我们评估了βig-h3作为监测慢性CyAN进展/消退的敏感尿液标志物的潜在作用。采用酶联免疫吸附测定法测定了9例慢性CyAN患者和13例移植肾功能稳定患者的尿βig-h3水平。我们对肾小管间质纤维化（TIF）的程度进行评分，并使用免疫过氧化物酶标记法测定慢性CyAN患者肾组织中βig-h3的表达。与对照组相比，慢性CyAN患者的尿βig-h3排泄量更高（173.4±26.0对62.6±5.0 ng/mg肌酐，P<0.01）。在慢性CyAN中，TIF的程度与尿βig-h3水平升高相关（r=0.785，P<0.05）。在患有慢性CyAN的肾脏中，βig-h3标记在炎症细胞浸润周围间质的肾小管基底膜（BM）处更为突出。此外，萎缩肾小管及其周围间质的BM被强烈标记。停用环孢素（CyA）或降低CyA剂量1个月后，尽管血清肌酐水平未变，但尿βig-h3水平从173.4±26.0降至64.9±14.4 ng/mg肌酐（P<0.01）。慢性CyAN患者的尿βig-h3水平在停用或降低CyA剂量后升高和降低。我们的结果表明，尿βig-h3水平可作为监测慢性CyAN进展或消退的敏感尿液标志物。
